JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia

Cachexia, the metabolic dysregulation leading to sustained loss of muscle and adipose tissue, is a devastating complication of cancer and other chronic diseases. Interleukin-6 and related cytokines are associated with muscle wasting in clinical and experimental cachexia, although the mechanisms by w...

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Vydáno v:	American journal of physiology: endocrinology and metabolism Ročník 303; číslo 3; s. E410
Hlavní autoři:	Bonetto, Andrea, Aydogdu, Tufan, Jin, Xiaoling, Zhang, Zongxiu, Zhan, Rui, Puzis, Leopold, Koniaris, Leonidas G, Zimmers, Teresa A
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 01.08.2012
Témata:	Animals Cachexia - etiology Cachexia - genetics Cachexia - pathology Cachexia - prevention & control Cells, Cultured CHO Cells Cricetinae Cricetulus Disease Models, Animal Female Interleukin-6 - genetics Interleukin-6 - metabolism Interleukin-6 - physiology Janus Kinases - antagonists & inhibitors Janus Kinases - genetics Janus Kinases - metabolism Male Mice Mice, Inbred C57BL Mice, Nude Mice, Transgenic Muscle, Skeletal - drug effects Muscle, Skeletal - metabolism Muscle, Skeletal - pathology Mutant Proteins - administration & dosage Mutant Proteins - genetics Neoplasms - complications Neoplasms - drug therapy Neoplasms - genetics Neoplasms - metabolism Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - pharmacology Pyrazoles - administration & dosage Pyrazoles - pharmacology RNA, Small Interfering - administration & dosage RNA, Small Interfering - pharmacology Signal Transduction - drug effects Signal Transduction - genetics STAT3 Transcription Factor - antagonists & inhibitors STAT3 Transcription Factor - genetics STAT3 Transcription Factor - metabolism Wasting Syndrome - genetics Wasting Syndrome - metabolism Wasting Syndrome - pathology Wasting Syndrome - prevention & control
ISSN:	1522-1555, 1522-1555
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Popis
Shrnutí:	Cachexia, the metabolic dysregulation leading to sustained loss of muscle and adipose tissue, is a devastating complication of cancer and other chronic diseases. Interleukin-6 and related cytokines are associated with muscle wasting in clinical and experimental cachexia, although the mechanisms by which they might induce muscle wasting are unknown. One pathway activated strongly by IL-6 family ligands is the JAK/STAT3 pathway, the function of which has not been evaluated in regulation of skeletal muscle mass. Recently, we showed that skeletal muscle STAT3 phosphorylation, nuclear localization, and target gene expression are activated in C26 cancer cachexia, a model with high IL-6 family ligands. Here, we report that STAT3 activation is a common feature of muscle wasting, activated in muscle by IL-6 in vivo and in vitro and by different types of cancer and sterile sepsis. Moreover, STAT3 activation proved both necessary and sufficient for muscle wasting. In C(2)C(12) myotubes and in mouse muscle, mutant constitutively activated STAT3-induced muscle fiber atrophy and exacerbated wasting in cachexia. Conversely, inhibiting STAT3 pharmacologically with JAK or STAT3 inhibitors or genetically with dominant negative STAT3 and short hairpin STAT3 reduced muscle atrophy downstream of IL-6 or cancer. These results indicate that STAT3 is a primary mediator of muscle wasting in cancer cachexia and other conditions of high IL-6 family signaling. Thus STAT3 could represent a novel therapeutic target for the preservation of skeletal muscle in cachexia.
Bibliografie:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Undefined-1 ObjectType-Feature-3 content type line 23
ISSN:	1522-1555 1522-1555
DOI:	10.1152/ajpendo.00039.2012